Professional Documents
Culture Documents
Current Treatment of Oral Candidiasis: A Literature Review
Current Treatment of Oral Candidiasis: A Literature Review
Current Treatment of Oral Candidiasis: A Literature Review
1
Dentist. Postgraduate in Oral Medicine
2
Associate profesor of Oral Medicine Unit. Department of Stomatology. University of Valencia
3
Chairman of Oral Medicine. Oral Medicine Unit. Department of Stomatology. University of Valencia. Head of the Department of
Stomatology and Maxilofacial Surgery. Valencia University General Hospital
Correspondence:
Avd. / Maestro Rodrigo 13-16 Garcia-Cuesta C, Sarrion-Pérez MG, Bagán JV. Current treatment of oral
46015 Valencia, Spain candidiasis: A literature review. J Clin Exp Dent. 2014;6(5):e576-82.
carlagcuesta@gmail.com http://www.medicinaoral.com/odo/volumenes/v6i5/jcedv6i5p576.pdf
Abstract
Candidiasis or oral candidosis is one of the most common human opportunistic fungal infections of the oral cavity.
This pathology has a wide variety of treatment which has been studied until these days. The present study offers
a literature review on the treatment of oral candidiasis, with the purpose of establish which treatment is the most
suitable in each case. Searching the 24 latest articles about treatment of candidiasis it concluded that the incidence
depends on the type of the candidiasis and the virulence of the infection. Although nystatin and amphotericin b were
the most drugs used locally, fluconazole oral suspension is proving to be a very effective drug in the treatment of
oral candidiasis. Fluconazole was found to be the drug of choice as a systemic treatment of oral candidiasis. Due
to its good antifungal properties, its high acceptance of the patient and its efficacy compared with other antifungal
drugs. But this drug is not always effective, so we need to evaluate and distinguish others like itraconazole or keto-
conazole, in that cases when Candida strains resist to fluconazole.
e576
J Clin Exp Dent. 2014;6(5):e576-82. Treatment of oral candidiasis
mans, which could act as an opportunistic pathogens of- tion; Appropriate use of antifungal drugs, evaluating the
ten associated with predisposing factors attributed to the efficacy / toxicity ratio in each case.
organism, thereby causing acute or chronic infections When choosing between some treatments it will take
(4). The most important of these species is C. albicans, into account the type of Candida, its clinical pathology
which is most commonly isolated from the oral cavity and if it is enough with a topical treatment or requires a
and is believed to be more virulent in humans, occurring more complex systemic type (8), always evaluating the
in approximately 50% of the cases of candidiasis. ratio efficacy and toxicity (9). The different drugs are
Clinically there are a number of different types of oral contained in table 3.
candidiasis (Table 2). Therefore the choice of therapy is Regular oral and dental hygiene with periodic oral exa-
guided by the type of candidiasis. mination will prevent most cases of oral candidiasis, so
The diagnosis of oral candidiasis is essentially clinical it is need to make the patient aware of oral hygiene mea-
and is based on the recognition of the lesions by the pro- sures. Oral hygiene involves cleaning the teeth, buccal
fessional, which can be confirmed by the microscopic cavity, tongue, and dentures. As well as the use of anti-
identification of Candida (5). The techniques available Candida rinses such as Chlorhexidine or Hexetidine, so
for the isolation of Candida in the oral cavity include that they can penetrate those areas where the brush does
direct examination or cytological smear, culture of mi- not. In addition, the need to remove the dentures at night
croorganisms and biopsy which is indicated for cases of and wash it consciously, leaving it submerged in a disin-
hiperplasic candidiasis because this type could present fectant solution like Chlorhexidine (10).
dysplasias (6). This study provides a literature review of the treatment
The treatment of oral candidiasis is based on four fun- of oral candidiasis and its objectives are to establish ge-
daments (7): making an early and accurate diagnosis of neral guidelines for treatment of oral candidiasis; Assess
the infection; Correcting the predisposing factors or un- the drug of choice for local treatment of oral candidiasis;
derlying diseases; Evaluating the type of Candida infec- Assess the systemic treatment for oral candidiasis.
Anfotericin b 50mg for infusion 100-200mg/6h Renal, cardiovascular, spinal and neurological
e577
J Clin Exp Dent. 2014;6(5):e576-82. Treatment of oral candidiasis
Material and Methods As first choice for local treatment has been for years the
A Medline-PubMed search was made using the fo- nystatin at doses of 100 000 IU/ml [5ml 4 times daily]
llowing key words: “ oral candidiasis” OR “oral candi- and amphotericin b at 50mg [5ml 3 times per day]. This
dosis” AND amphotericin, “oral candidiasis” OR “oral choice is because they are poorly absorbed by the in-
candidosis” AND nystatine, “oral candidiasis” OR “oral testinal tract and therefore most of the antifungal is ex-
candidosis” AND miconazole, “oral candidiasis” OR creted without undergoing any change, thereby reducing
“oral candidosis” AND ketoconazole, “oral candidiasis” hepatotoxicity (14). However, the unpleasant taste and
OR “oral candidosis” AND clotrimazole, “oral candidia- prolonged pattern compromise treatment compliance by
sis” OR “oral candidosis” AND fluconazole, “oral can- the patient (14-16).
didiasis” OR “oral candidosis” AND itraconazole, “oral Throughout the years it has been studying the effective-
candidiasis” OR “oral candidosis” AND treatment, “oral ness of other drugs like fluconazole oral solution. Many
candidiasis” OR “oral candidosis” AND “antifungal authors have focused on evaluating the efficacy and
therapy”.The key words were validated by the MeSH safety of fluconazole oral solution for the treatment of
[Medical Subject Headings] dictionary, with use of the oropharyngeal candidiasis, especially pseudomembra-
boolean operator “AND” to relate them. nous type, giving good results, although many studies
The following limits for inclusion of the studies were esta- are still needed (14-18).
blished: articles published from 2000, publications in En- In a recent study conducted in 19 patients with pseudo-
glish and Spanish and publications of studies in humans. membranous candidiasis show that fluconazole suspen-
All systematic reviews, clinical trials, meta-analysis and sion in distilled water [2mg/ml] reaches a 95% cure.
comparative studies were considered in this review. The guideline was to rinse with 5ml of the drug solution
A total of 109 articles were identified, of which 30 were for 1 minute and then spit it out and repeat this action
selected after reading the abstracts. Following analysis 3 times a day for 1 week. Another study which inclu-
of the 30 articles, we finally included a total of 24, since ded 36 children with pseudomembranous candidiasis
those publications that did not fit the aims of the present showed that fluconazole oral suspension 10mg/ml dose
study were excluded. gave better results than nystatin. The main problem was
the poor adherence of the nystatin to the oral mucosa and
Results thus the quick ingestion of the suspension, resulting in a
A total of 24 articles were found about antifungal lower efficiency (14).
treatment, of which 20 were clinical trials, 3 systematic On the other hand, in another study comparing amphote-
reviews and 1 a clinical case (Table 4, 4 (Cont)). ricin b suspension, the fluconazole oral suspension gave
better results in terms of the eradication of Candida (16).
The same was corroborated by Taillandier et al. (18),
Discussion
which reported that fluconazole oral suspension was as
Candida infection today is highly prevalent, especia-
effective as amphotericin b, but it was better accepted
lly the increase in carriers of removable dentures and
by the patient.
poor oral hygiene society. Depending on its virulence,
Fluconazole oral suspension is administered in a dosage
location and type of candidiasis there will carry on one
of 10 mg / ml aqueous suspension by administering 5 ml
treatment or another.
daily for 7 or 14 days. Different studies show that it is
First has been supported the use of conservative mea-
a very effective drug against pseudomembranous candi-
sures before starting drug treatment, promoting good
diasis, as it has good adhesion to the surface of the oral
oral hygiene along with removing the dentures at night,
mucosa and a rapid symptomatic response. It also offers
thereby it will benefit the removal of the biofilm layer
the convenience of a one-daily dosing, which may ex-
generated in the prosthetic surface (11). Dentists should
plain the better patient compliance (14-18).
also correct the predisposing factors and underlying di-
Another topic drug widely used is miconazole (19).
seases and try to promote the use of oral antiseptic and
We found it in the form of gel, applying it directly on
antibacterial rinses such as Chlorhexidine or Hexetidine
the affected area, at doses of 200-500 mg per day, divi-
(12). These measures are very effective in patients with
ded into 4 times. Despite its good properties it has the
denture stomatitis (12). It was also found in the study of
drawback of possible interaction with other drugs, such
Cross et al. (13) that in patients with good oral hygiene
as warfarin. This is because the antifungal inhibit the en-
the recurrence of candidiasis after 3 years was lower.
zyme cytochrome P-450, which affects the clearance of
Regarding the pharmacological treatment of candidiasis
certain drugs (20,21). In addition, this drug is absorbed
can be distinguished between two procedures. Topical
by the intestine, therefore care must be taken when is
drugs, which are applied to the affected area and treat
administrated.
superficial infections and systemic drugs those that are
It has been introduced in the market an alternative pre-
prescribed when the infection is more widespread and
sentation of miconazole. A one-daily miconazole 50 mg
has not been enough with the topical therapy.
e578
J Clin Exp Dent. 2014;6(5):e576-82. Treatment of oral candidiasis
e579
J Clin Exp Dent. 2014;6(5):e576-82. Treatment of oral candidiasis
e580
J Clin Exp Dent. 2014;6(5):e576-82. Treatment of oral candidiasis
mucoadhesive buccal tablet. It has a limited systemic zole capsules. But when fluconazole failed, itraconazole
absorption. Its performance is mostly local and it has a was prescribed to these patients, having good results. So
convenient application form. Patients are instructed to it is said that it was a good drug for fluconazole-resistant
apply the rounded side of the 50 mg tablet to the upper Candida strains (29).
gum region just above the right or left incisor following As it has been suggested above, it may happen that the
brushing of teeth in the morning. The tablet should be Candida strains were not susceptible to fluconazole, and
held in place until dissolved (22,23). It has the advanta- it has not any effect. In that case it will be used other drugs
ge of being applied once daily instead 5 times a day with like itraconazole or newest ones as voriconazole (30).
clotrimazole (24), and 4 times daily with nystatin (25). Keeping always in mind that strains which were resistant
It has been demonstrated the effectiveness of this new to fluconazole were also resistant to other drugs (31).
form of administration in the study of Bensadoun et al. The new triazol antifungal voriconazole [200 mg per
(26). 141 patients with head and neck cancer with cli- day] has been shown to be a potent drug. Ally et al. (32)
nical signs and symptoms of oropharyngeal candidiasis compared the efficacy of voriconazole and fluconazole
received 50 mg mucoadhesive tablets of miconazole in the treatment of esophageal candidiasis. The success
daily or 125 mg miconazole gel four times per day. Cli- rate was 98.3% for voriconazole and 95.1% for fluco-
nical improvement was not significant between the two nazole. The results show clearly that voriconazole is at
groups, but the mucoadhesive tablets exhibited higher least as effective as fluconazole in the treatment of can-
salivary concentrations and better tolerance for the pa- didiasis. It suggests that this new agent may be a use-
tient. Despite being more expensive, offers an effective, ful alternative for fluconazole-resistant Candida strains
safe, and well tolerated topical treatment for oropharyn- (32). Because of being a new there are little strains resis-
geal candidiasis (22,23,26). tant to voriconazole. The voriconazole has an important
- Systemic treatment: role in the treatment of candidiasis (30), although it is
In spite of knowing the efficacy of the drugs listed abo- still not fully established in the market, so many more
ve, when it comes to a more generalized candidiasis or studies and research would be needed.
immunocompromised patients, these would not be suffi- There have been several studies comparing topical and
cient. For those cases would have to resort to treatment systemic drugs. In a study to treat denture stomatitis have
with systemic drugs (25). been compared the use of ketoconazole tablets [200mg
Since its introduction, fluconazole has been used to treat daily] with topical ketoconazole [2% twice daily] and
systemic Candida infections because of its efficacy and miconazole mucoadhesive tablets (33). Due to the ad-
good tolerability. The appropriate dose is between 50- verse effects of ketoconazole (31) like nausea, vomiting
100 mg daily (27). Furthermore, when dealing with im- and gastrointestinal problems it has been supported the
munocompromised patients, such as those HIV-infected, use of other drugs when treating prosthetic candidiasis
or cancerous, this drug has good effects doubling the (34). Thus the use of miconazole mucoadhesive tablet
dose (28,29). Its efficacy has been demonstrated (27). was established as the drug of first line of defense for
The dose was individualized depending on the severity this type of candidiasis.
and type of candidiasis. Patients with pseudomembra- General treatment guidelines include after the comple-
nous type started with 100 mg fluconazole daily; patients tion of an early diagnosis, the correction of predisposing
with erythematous variety started with 50 mg fluconazo- factors or underlying diseases and maintaining a good
le. Therefore, according to the clinic and the virulence oral hygiene. Moreover using antiseptic agents such as
of the infection the dose would be titrated, giving good Chlorhexidine or Hexetidine, as well as removing den-
results, and increasing the guideline in those cases whe- tures at night. All of that in order to obtain well results in
re the fungal infection did not decrease (27). the treatment of oral candidiasis as first line of defense,
To support the efficacy of this drug it has been compared continuing the application of antifungal drugs. Begin-
with other systemic antifungal agents (29). In one ran- ning with local treatment and keeping up the systemic
domized study, the efficacy of fluconazole [100mg per ones for those patients who do not respond to topical
day for 10 days] and itraconazole [200mg per day for treatment or in immunocompromised patients.
15 days] was compared in patients with oropharyngeal It has recently been found that fluconazole oral suspen-
candidiasis. The results were a clinical and mycologi- sion as a local treatment, at a dose of 2 mg/ml 3 times
cal improvement of 66% for the first group and 54% for daily or 10 mg /ml once daily, gives good clinical results,
those treated with itraconazole. The main conclusion of besides the better patient compliance due to the dosage
this study is that in patients with oropharyngeal candi- and its pleasant taste. Despite not being currently the
diasis, fluconazole has a significantly better clinical and most widely used locally because it requires further cli-
mycological cure rate compared with itraconazole. The nical studies. Nowadays the most used drugs remains in
failures of itraconazole may be explained by drug in- nystatin solution which contain 100 000 IU / ml [5ml 4
teractions and the unpredictable absorption of itracona- times daily] and miconazole gel [200 to 500 mg per day
e581
J Clin Exp Dent. 2014;6(5):e576-82. Treatment of oral candidiasis
divided into 4 doses]. Moreover miconazole mucoad- 19. Isham N, Ghannoum MA. Antifungal activity of miconazole
hesive tablets [50 mg once daily] which are considered against recent Candida strains. Mycoses. 2010;53:434-7.
20. Pemberton MN, Oliver RJ, Theaker ED. Miconazole oral gel and
effective in the treatment of oropharyngeal candidiasis, drug interactions. Br Dent J. 2004;196:529-31.
but their high cost is one of the main problems. 21. Miki A, Ohtani H, Sawada Y. Warfarin and miconazole oral gel
Fluconazole at doses between 50-100 mg per day is the interactions: analysis and therapy recommendations based on clinical
systemic drug of choice because it has high efficacy and data and a pharmacokinetic model. J Clin Pharm Ther. 2011;36:642-
50.
tolerability by the patient. However it is important to 22. Collins CD, Cookinham S, Smith J. Management of oropharyngeal
think about the voriconazole which is as effective as flu- candidiasis with localized oral miconazole therapy: efficacy, safety,
conazole but is still under study. Also it is need to know and patient acceptability. Patient Prefer Adherence. 2011;5:369-74.
about other drugs such as itraconazole, which are effec- 23. Vazquez JA, Sobel JD. Miconazole mucoadhesive tablets: a novel
delivery system. Clin Infect Dis. 2012;54:1480-4.
tive when Candida strains are resistant to fluconazole. 24. Czerninski R, Sivan S, Steinberg D, Gati I, Kagan L, Friedman M.
A novel sustained-release clotrimazole varnish for local treatment of
References oral candidiasis. Clin Oral Investig. 2010;14:71-8.
1. Arendrup MC, Fuursted K, Gahrn-Hansen B, Jensen IM, Knudsen 25. Oji C, Chukwuneke F. Evaluation and treatment of oral candidia-
JD, Lundgren B, et al. Seminational surveillance of fungemia in Den- sis in HIV/AIDS patients in Enugu, Nigeria. Oral Maxillofac Surg.
mark: notably high rates of fungemia and numbers of isolates with 2008;12:67-71.
reduced azole susceptibility. J Clin Microbiol. 2005;43:4434-40. 26. Bensadoun RJ, Daoud J, El Gueddari B, Bastit L, Gourmet R, Ro-
2. Rodloff C, Koch D, Schaumann R. Epidemiology and antifungal sikon A, et al. Comparison of the efficacy and safety of miconazole 50-
resistance in invasive candidiasis. Eur J Med Res. 2011;16:187-95. mg mucoadhesive buccal tablets with miconazole 500-mg gel in the
3. Thompson GR 3rd, Patel PK, Kirkpatrick WR, Westbrook SD, Berg treatment of oropharyngeal candidiasis: a prospective, randomized,
D, Erlandsen J, et al. Oropharyngeal candidiasis in the era of antire- single-blind, multicenter, comparative, phase III trial in patients trea-
troviral therapy. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. ted with radiotherapy for head and neck cancer. Cancer. 2008;112:204-
2010;109:488-95. 11.
4. Williams DW, Kuriyama T, Silva S, Malic S, Lewis MA. Candida 27. Koks CH, Crommentuyn KM, Mathôt RA, Mulder JW, Meenhorst
biofilms and oral candidosis: treatment and prevention. Periodontol PL, Beijnen JH. Prognostic factors for the clinical effectiveness of flu-
2000. 2011;55:250-65. conazole in the treatment of oral candidiasis in HIV-1-infected indivi-
5. Coronado-Castellote L, Jiménez-Soriano Y. Clinical and microbiolo- duals. Pharmacol Res. 2002;46:89-94.
gical diagnosis of oral candidiasis. J Clin Exp Dent. 2013;5:e279-86. 28. Lyon JP, de Resende MA. Correlation between adhesion, enzy-
6. Byadarahally Raju S, Rajappa S. Isolation and identification of Can- me production, and susceptibility to fluconazole in Candida albicans
dida from the oral cavity. ISRN Dent. 2011;2011:487921. obtained from denture wearers. Oral Surg Oral Med Oral Pathol Oral
7. Aguirre Urizar JM. Oral Candidiasis. Rev Iberoam Micol. 2002;19:17- Radiol Endod. 2006;102:632-8.
21. 29. Oude Lashof AM, De Bock R, Herbrecht R, de Pauw BE, Krcmery
8. Williams D, Lewis M. Pathogenesis and treatment of oral candido- V, Aoun M, et al.; EORTC Invasive Fungal Infections Group. An open
sis. J Oral Microbiol. 2011;28:3. multicentre comparative study of the efficacy, safety and tolerance of
9. Martínez-Beneyto Y, López-Jornet P, Velandrino-Nicolás A, Jornet- fluconazole and itraconazole in the treatment of cancer patients with
García V. Use of antifungal agents for oral candidiasis: results of a oropharyngeal candidiasis. Eur J Cancer. 2004;40:1314-9.
national survey. Int J Dent Hyg. 2010;8:47-52. 30. Kuriyama T, Williams DW, Bagg J, Coulter WA, Ready D, Lewis
10. Akpan A, Morgan R. Oral candidiasis. Postgrad Med J. MA. In vitro susceptibility of oral Candida to seven antifungal agents.
2002;78:455-9. Oral Microbiol Immunol. 2005;20:349-53.
11. Manfredi M, Polonelli L, Aguirre-Urizar JM, Carrozzo M, Mc- 31. Brito GN, Inocêncio AC, Querido SM, Jorge AO, Koga-Ito CY. In
Cullough MJ. Urban legends series: oral candidosis. Oral Dis. vitro antifungal susceptibility of Candida spp. oral isolates from HIV-
2013;19:245-61. positive patients and control individuals. Braz Oral Res. 2011;25:28-
12. Koray M, Ak G, Kurklu E, Issever H, Tanyeri H, Kulekci G, et al. 33.
Fluconazole and/or hexetidine for management of oral candidiasis as- 32. Ally R, Schürmann D, Kreisel W, Carosi G, Aguirrebengoa K,
sociated with denture-induced stomatitis. Oral Dis. 2005;11:309-13. Dupont B, et al. Esophageal Candidiasis Study Group. A randomized,
13. Cross LJ, Williams DW, Sweeney CP, Jackson MS, Lewis MA, double-blind, double-dummy, multicenter trial of voriconazole and
Bagg J. Evaluation of the recurrence of denture stomatitis and Candida fluconazole in the treatment of esophageal candidiasis in immunocom-
colonization in a small group of patients who received itraconazole. promised patients. Clin Infect Dis. 2001;33:1447-54.
Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2004;97:351-8. 33. Khozeimeh F, Shahtalebi MA, Noori M, Savabi O. Comparative
14. Goins RA, Ascher D, Waecker N, Arnold J, Moorefield E. Compa- evaluation of ketoconazole tablet and topical ketoconazole 2% in ora-
rison of fluconazole and nystatin oral suspensions for treatment of oral base in treatment of Candida-infected denture stomatitis. J Contemp
candidiasis in infants. Pediatr Infect Dis J. 2002;21:1165-7. Dent Pract. 2010;11:017-24
15. Epstein JB, Gorsky M, Caldwell J. Fluconazole mouthrinses for 34. Van Roey J, Haxaire M, Kamya M, Lwanga I, Katabira E. Com-
oral candidiasis in postirradiation, transplant, and other patients. Oral parative efficacy of topical therapy with a slow-release mucoadhesive
Surg Oral Med Oral Pathol Oral Radiol Endod. 2002;93:671-5. buccal tablet containing miconazole nitrate versus systemic therapy
16. Lefebvre JL, Domenge C; Study Group of Mucositis. A compara- with ketoconazole in HIV-positive patients with oropharyngeal candi-
tive study of the efficacy and safety of fluconazole oral suspension and diasis. J Acquir Immune Defic Syndr. 2004;35:144-50.
amphotericin B oral suspension in cancer patients with mucositis. Oral
Oncol. 2002;38:337-42.
17. Sholapurkar AA, Pai KM, Rao S. Comparison of efficacy of flu- Conflict of Interest
conazole mouthrinse and clotrimazole mouthpaint in the treatment of The authors declare that they have no conflict of interest.
oral candidiasis. Aust Dent J. 2009;54:341-6.
18. Taillandier J, Esnault Y, Alemanni M. A comparison of fluconazole
oral suspension and amphotericin B oral suspension in older patients
with oropharyngeal candidosis. Multicentre Study Group. Age Age-
ing. 2000;29:117-23.
e582